Faculty Bibliography

Single-cell RNA sequencing (scRNA-seq) enables the systematic identification of cell populations in a tissue, but characterizing their spatial organization remains challenging. We combine a microarray-based spatial transcriptomics method that reveals spatial patterns of gene expression using an array of spots, each capturing the transcriptomes of multiple adjacent cells, with scRNA-Seq generated from the same sample. To annotate the precise cellular composition of distinct tissue regions, we introduce a method for multimodal intersection analysis. Applying multimodal intersection analysis to primary pancreatic tumors, we find that subpopulations of ductal cells, macrophages, dendritic cells and cancer cells have spatially restricted enrichments, as well as distinct coenrichments with other cell types. Furthermore, we identify colocalization of inflammatory fibroblasts and cancer cells expressing a stress-response gene module. Our approach for mapping the architecture of scRNA-seq-defined subpopulations can be applied to reveal the interactions inherent to complex tissues.

Squamous cell carcinoma (SCC) of the colon is an exceedingly rare clinical diagnosis with few cases reported in the literature. We report a case of a 61-year-old man with a medical history of cutaneous SCC of the penis who presented with hematochezia and was found to have metastatic SCC to the distal transverse colon. To our knowledge, this is the first case of colonic SCC presenting as a metastatic disease from a primary penile site.

INTRODUCTION: Cystoisosporiasis is an underrecognized gallbladder infection of immunocompetent hosts due in part to subtle histopathologic findings and low index of suspicion during examination of routine cholecystectomy specimens. This case will highlight the importance of detecting the organism in order to gain understanding of its life cycle and to raise awareness of the potential symptoms for those who become immunosuppressed. CASE DESCRIPTION/METHODS: A 65-year-old male with compensated cirrhosis presented with complaints of intermittent right upper quadrant pain for three months. He denied symptoms of diarrhea, jaundice, fever, chills, recent travel and sick contacts. CBC, BMP and liver enzymes were unremarkable. A right upper quadrant ultrasound illustrated multiple gallstones within the gallbladder along with wall thickening measuring up to 4.8 mm. The patient underwent a laparoscopic cholecystectomy with resolution of symptoms. Pathologic evaluation of the resected gallbladder described elongated "banana-shaped" zoites of C. belliwithin parasitopherous vacuoles in the gallbladder columnar mucosa. DISCUSSION: Cystoisospora belli (C. belli) is an intracellular protozoan of the intestinal epithelium often associated with gastrointestinal (GI) disease in immunocompromised patients or those who travel to endemic areas. The infection is acquired by fecal-oral route through ingestion of infective oocysts in contaminated water. Symptoms of C. belli include watery diarrhea, abdominal pain, nausea, vomiting and weight loss due to malabsorption, whereas most infected immunocompetent patients remain asymptomatic. C. belli is known to reside within parasitophorous vacuoles in epithelial cells of the small intestine; however, incidence of gallbladder infection is on the rise as there becomes an increased awareness and recognition on the part of the pathologist. Previously, lack of recognition has stemmed from multiple factors including a low index of suspicion in patients without clinical symptoms or those who remain immunocompetent, the underwhelming appearance of infected gallbladders with lack of significant tissue reaction, as well as the sparse distribution of the organisms themselves. The unexpectedly high prevalence in gallbladder specimens has given rise to the idea that the gallbladder may be an anatomic reservoir for this commensal organism in the immunocompetent host. For this reason, C. belli infection should be considered in patients exhibiting typical GI symptoms following immunosuppression. (Figure Presented)

INTRODUCTION: The majority of "giant" hemangiomas remain asymptomatic with no cause for surgical intervention; however, this may not hold true for massive tumors. The following case will review the challenges facing both patients and physicians when managing these atypical tumors. CASE DESCRIPTION/METHODS: A 49-year-old male with no medical problems presented with complaints of post-prandial bloating, early satiety and mild epigastric discomfort. The bloating was intermittent for several years; however, symptoms have recently curtailed his eating habits. CBC, BMP and liver enzymes were unremarkable. An ultrasound highlighted a massively enlarged liver extending into the pelvis and displacing surrounding organs. The liver parenchyma appeared to be replaced with a homogenous, hyperechoic lesion. An MRI then illustrated a 29.5x20.1x19.4 cm, strongly hyperintense mass on T-2 weighted sequences consistent with the diagnosis of a hemangioma. He was referred to a hepatobiliary surgeon and an extended right hepatectomy was eventually performed. Histopathology results described vast endothelial lined channels supported by thin fibrous stroma without features of malignancy. The patient returned to clinic four weeks after surgery reporting complete resolution of his symptoms. DISCUSSION: Hemangiomas are the most common benign solid tumor of the liver with little to no risk of malignant transformation. Often discovered incidentally on imaging studies, the majority of these tumors remain indolent without the need for routine surveillance. Rarely these tumors become symptomatic, often correlating with tumor size. The definition of "giant" liver hemangioma remains controversial, with most authors assigning the label to tumors greater than 4cm or 5cm in size. It is for this reason that management of giant hemangiomas remains highly debated (i.e. observation versus resection). Recent studies have shown that tumors greater than 20cm in size pose a higher risk for GI symptoms related to mass effect on surrounding organs as well as causing a disturbance in the hematologic and coagulation systems. Surgical resection should be considered for symptomatic or complicated lesions, or when the diagnosis remains inconclusive. It is our belief that size classifications for giant hemangiomas requires further subgrouping to consider the danger of these massive tumors as well as the increased morbidity of surgery. Proper management of these tumors should be individualized to each patient and include [2259] Figure 1. a multidisciplinary team approach. (Figure Presented)

Pancreatic neuroendocrine tumors (PNETs) occur in the context of tuberous sclerosis complex (TSC). To date, PNETs in association with TSC have been described almost exclusively in adults and in the context of TSC2. We present the evaluation of a PNET in a young child with TSC1. A 3-year, 6-month-old boy with TSC1 was found on surveillance to have a small pancreatic lesion measuring 0.4 cm on magnetic resonance imaging (MRI). The lesion showed interval enlargement to 1 cm on serial MRI studies during the ensuing 16 weeks. Endocrine laboratory tests did not reveal a functional tumor. The patient underwent enucleation of the pancreatic lesion. Microscopic examination defined a well-differentiated PNET, grade II/intermediate grade with a mitotic rate of two mitotic figures per 10 high-powered field and Ki-67 proliferation index of ∼15%. The tumor was positive for the TSC1 gene mutation. The patient was free of tumor recurrence at the 5-year follow-up examination, as determined by endocrine surveillance and annual MRI of the abdomen. In the reported data, PNET in patients with TSC has been primarily reported in association with TSC2. Our case demonstrates that patients with TSC1 can develop PNETs, even at an early age. The international TSC consensus group 2012 recommendation was to obtain MRI of the abdomen every 1 to 3 years for surveillance of renal angiomyolipomas and renal cystic disease. It might be beneficial to add a pancreatic protocol to the surveillance guidelines to evaluate for PNET.

We present an 81-year-old woman with remote breast cancer who presented with melena and hemorrhagic shock requiring intensive care hospitalization. Endoscopic evaluation showed a 5-cm pedunculated gastric mass with ulceration and friability. She underwent sleeve gastrectomy for definitive treatment of her bleeding. Pathology was consistent with a solitary fibrous tumor (SFT). There are only a few reported cases of gastric SFTs presenting with gastrointestinal bleeding. If a large brown/tan bleeding mass is identified on upper endoscopy, SFT should be considered.

Through the action of two virus-encoded decapping enzymes (D9 and D10) that remove protective caps from mRNA 5'-termini, Vaccinia virus (VACV) accelerates mRNA decay and limits activation of host defenses. D9- or D10-deficient VACV are markedly attenuated in mice and fail to counter cellular double-stranded RNA-responsive innate immune effectors, including PKR. Here, we capitalize upon this phenotype and demonstrate that VACV deficient in either decapping enzyme are effective oncolytic viruses. Significantly, D9- or D10-deficient VACV displayed anti-tumor activity against syngeneic mouse tumors of different genetic backgrounds and human hepatocellular carcinoma xenografts. Furthermore, D9- and D10-deficient VACV hyperactivated the host anti-viral enzyme PKR in non-tumorigenic cells compared to wild-type virus. This establishes a new genetic platform for oncolytic VACV development that is deficient for a major pathogenesis determinant while retaining viral genes that support robust productive replication like those required for nucleotide metabolism. It further demonstrates how VACV mutants unable to execute a fundamental step in virus-induced mRNA decay can be unexpectedly translated into a powerful anti-tumor therapy.